Delivery systems containing bioactive materials

ABSTRACT

A delivery system comprising a covering containing at least a first substance for release to a surgical site is provided. The covering includes an elongated containment portion having at least one compartment, wherein the covering includes an elongated containment having a first end and a second end. At one end the elongated containment defines an opening configured to receive at least one substance. The at least one substance can be DBM or a mixture of demineralized fibers and particles in a ratio of 30:70. The delivery system also includes a closing member that can close the elongated containment prior to insertion at a surgical site. The closing member can be drawing strings, stitches, sutures, wing sutures, heat seals, adhesion, pressure fittings, coil ring, twist tie. The substance contained in the delivery system can also be enclosed by twisting and folding over a portion of the covering.

This application is a divisional application of U.S. patent applicationSer. No. 13/740,357 filed Jan. 14, 2013, entitled “DELIVERY SYSTEMSCONTAINING BIOACTIVE MATERIALS,” now U.S. Pat. No. 9,034,052. Thepresent application claims the benefit of the filing date of theaforementioned application and its disclosure is hereby incorporated byreference it its entirety.

FIELD

A delivery system for delivering a substance or material to a surgicalsite is provided. More particularly, a delivery system comprising acovering, a substance, and a closing member.

BACKGROUND

The use of bone grafts and bone substitute materials in orthopedicmedicine is known. While bone wounds can regenerate without theformation of scar tissue, fractures and other orthopedic injuries take along time to heal, during which time the bone is unable to supportphysiologic loading unaided. Metal pins, screws, rods, plates and meshesare frequently required to replace the mechanical functions of injuredbone. However, metal is significantly more stiff than bone. Use of metalimplants may result in decreased bone density around the implant sitedue to stress shielding. Physiologic stresses and corrosion may causemetal implants to fracture. Unlike bone, which can heal small damagecracks through remodeling to prevent more extensive damage and failure,damaged metal implants can only be replaced or removed. The naturalcellular healing and remodeling mechanisms of the body coordinateremoval of bone and bone grafts by osteoclast cells and formation ofbone by osteoblast cells.

Conventionally, bone tissue regeneration is achieved by filling a bonerepair site with a bone graft. Over time, the bone graft is incorporatedby the host and new bone remodels the bone graft. In order to place thebone graft, it is common to use a monolithic bone graft or to form anosteoimplant comprising particulated bone in a carrier. The carrier isthus chosen to be biocompatible, to be resorbable, and to have releasecharacteristics such that the bone graft is accessible.

The rapid and effective repair of bone defects caused by injury,disease, wounds, or surgery is a goal of orthopedic surgery. Toward thisend, a number of compositions and materials have been used or proposedfor use in the repair of bone defects. The biological, physical, andmechanical properties of the compositions and materials are among themajor factors influencing their suitability and performance in variousorthopedic applications.

Demineralized bone matrix (“DBM”) implants have been reported to beparticularly useful. Demineralized bone matrix is typically derived fromcadavers. The bone is removed aseptically and/or treated to kill anyinfectious agents. The bone is then particulated by milling or grindingand then the mineral components are extracted for example, by soakingthe bone in an acidic solution.

Current DBM formulations have various drawbacks. First, while thecollagen-based matrix of DBM is relatively stable, the active factorswithin the DBM matrix are rapidly degraded. The osteogenic activity ofthe DBM may be significantly degraded within 24 hours afterimplantation, and in some instances the osteogenic activity may beinactivated within 6 hours. Therefore, the factors associated with theDBM are only available to recruit cells to the site of injury for ashort time after transplantation. For much of the healing process, whichmay take weeks to months, the implanted material may provide little orno assistance in recruiting cells.

Attempts to overcome these problems have lead researchers to utilizedelivery systems such as polymer mesh bags or pouches to release DBM ata surgical site. Pouch closure is typically done by suturing, which isoften time consuming and may require special equipment to bring aboutpouch closure.

Thus, there is a need to improve the efficacy and consistency of DBMdelivery systems by utilizing more expeditious and simpler approaches toclosing the open end of a DBM containing polymer mesh bag.

SUMMARY

A delivery system for delivering a substance or material to a surgicalsite is provided. The delivery system comprises a covering and asubstance to be retained within and delivered by the covering.Generally, the covering may be at least a single compartment capable ofretaining a substance provided therein until the covering is placed at asurgical site. In some examples, upon placement, the coveringfacilitates transfer of the substance and/or materials from the coveringto the surgical site. The covering may participate in, control, orotherwise adjust, the release of the substance or penetration of thecovering by surrounding materials, such as cells or tissues.

In certain embodiments the covering of the delivery system includes anelongated containment portion having at least one compartment and atleast a first substance which can be mixed with another substance priorto delivery at a surgical site. The first substance can be particles,fibers or chips of demineralized bone matrix (DBM) and the secondsubstance can be bone graft material such as autologous milled boneparticles and growth factors.

In some embodiments, the delivery system comprises a closing member thatcan be attached at any location along the elongated container. Invarious embodiments, the closing member can be attached at a locationeffective to define an upper and lower portion of the elongatedcontainment. In other embodiments, after securing the elongatedcontainment with the closing member, the upper portion can be foldedover the lower portion of the elongated containment. In yet otherembodiments, the upper portion of the elongated containment can befolded over the lower portion in the absence of a closing member, simplyby twisting the upper portion at a selected location and folding overthe lower portion of the elongated containment.

In various embodiments, the closing member comprises drawing strings,stitches, sutures, wing sutures, heat seals, adhesion, pressurefittings, coil ring, twist tie or combinations thereof. In certainembodiments, either the covering or the closing member or both comprisea material selected from bioerodible polymers, bioabsorbable polymers,biodegradable biopolymers, synthetic polymers, copolymers orcombinations thereof.

In some embodiments, the elongated containment portion has a crosssectional shape selected from generally circular or generally oval and ashape that can be tubular, rectangular, or cubic. The covering can havetwo ends opposite each other and be made from porous mesh to provide,for example, a porous mesh bag.

In various embodiments, the at least one compartment is unfilled atmanufacture but configured to be filled prior to or during the surgicalprocedure.

In other embodiments, the at least one compartment of the deliverysystem can be filled with autograft or allograft. In certainembodiments, the at least one substance in the at least one compartmentcomprises demineralized bone matrix fibers and particles in a ratio ofabout 30:70.

In various embodiments, a second substance can be added to the deliverysystems described herein includes protein, bone morphogenetic proteins,carbohydrate, lipids, collagen, allograft bone, autograft bone,tricalcium phosphate, hydroxyapatite, growth and differentiationfactors, carriers for growth factors, growth factors extracts of tissue,bone marrow aspirate, concentrates of lipid derived or marrow derivedadult stem cells, umbilical cord derived stem cells, committed orpartially committed cells from osteogenic or chondrogenic lineage,antimicrobials, antibiotics, or combinations thereof.

In certain embodiments, a delivery system comprising a coveringconfigured for implantation into a bone defect site is provided. Thecovering contains at least one compartment having an elongatedcontainment with a first end and second end opposite each other, theelongated containment defining an opening configured to receive at leastone substance. In many embodiments, the elongated containment is adaptedto receive slidably a closing member at a selected location along theelongated containment, the selected location effective to define aroundthe closing member an upper and a lower portion of the containment, theupper portion foldable over the lower portion.

In various embodiments, the present application provides a method forpreparing a delivery system comprising a covering for implantation intoa bone defect. The method for preparing the delivery system comprisesproviding the covering having an elongated containment and defining anopening at one end, the opening configured for receiving at least onesubstance. Subsequently, the method includes filling the elongatedcontainment with the at least one substance, closing the elongatedcontainment with a closing member at a selected location along theelongated containment, and implanting the closed delivery system into abone defect.

The present application also provides a method for treating a bonedefect in a patient in need of such treatment. The method of treatmentcomprises implanting into the bone defect all or at least a portion of acovering comprising one or more biodegradable polymers, the coveringbeing porous and comprising at least one compartment, the at least onecompartment comprising an elongated containment, which elongatedcontainment defines an opening configured to receive at least onesubstance, the elongated containment adapted to receive slidably aclosing member at a selected location along the elongated containment.

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingdrawings. While the invention will be described in conjunction with theillustrated embodiments, it will be understood that they are notintended to limit the invention to those embodiments. On the contrary,the invention is intended to cover all alternatives, modifications, andequivalents that may be included within the invention as defined by theappended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In part, other aspects, features, benefits and advantages of theembodiments will be apparent with regard to the following description,appended claims and accompanying drawings where:

FIG. 1 illustrates a side view of a delivery system comprising acovering having an elongated containment portion, a sealed end, an openend and a closing member in accordance with one embodiment of thepresent disclosure;

FIG. 2 illustrates a side view of a delivery system comprising acovering such as a porous mesh bag having an elongated containment and aclosing member defining an upper portion of the containment and a lowerportion of the containment accordance with another embodiment of thepresent disclosure;

FIG. 3 illustrates a top view of a delivery system comprising a coveringhaving an elongated containment and a closing member, wherein the upperportion of the containment is folded over the lower portion of thecontainment in accordance with an embodiment of the present disclosure;

FIG. 4 illustrates a side view of a delivery system comprising acovering such as a mesh bag comprising a closed end and an open end thatcan be closed by draw strings in accordance with another embodiment ofthe present disclosure;

FIG. 5 illustrates a side view of the delivery system comprising a meshbag having an open end that can be closed by draw strings in accordancewith another embodiment of the present disclosure;

FIG. 6 illustrates side view of the delivery system wherein the drawstring is positioned about midway the elongated container in accordancewith another embodiment of the present disclosure;

FIG. 7 illustrates a top view of a delivery system according to anotheraspect of the present application;

FIG. 8 illustrates a top view of a delivery system according to yetanother aspect of the present application.

It is to be understood that the figures are not drawn to scale. Further,the relation between objects in a figure may not be to scale, and may infact have a reverse relationship as to size. The figures are intended tobring understanding and clarity to the structure of each object shown,and thus, some features may be exaggerated in order to illustrate aspecific feature of a structure.

DETAILED DESCRIPTION

For the purposes of this specification and appended claims, unlessotherwise indicated, all numbers expressing quantities of ingredients,percentages or proportions of materials, reaction conditions, and othernumerical values used in the specification and claims, are to beunderstood as being modified in all instances by the term “about.”Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the present invention. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical parameter shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques.

Notwithstanding the numerical ranges and parameters set forth herein,the broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Moreover, all ranges disclosed hereinare to be understood to encompass any and all subranges subsumedtherein. For example, a range of “1 to 10” includes any and allsubranges between (and including) the minimum value of 1 and the maximumvalue of 10, that is, any and all subranges having a minimum value ofequal to or greater than 1 and a maximum value of equal to or less than10, e.g., 5.5 to 10.

The headings below are not meant to limit the disclosure in any way;embodiments under any one heading may be used in conjunction withembodiments under any other heading.

DEFINITIONS

It is noted that, as used in this specification and the appended claims,the singular forms “a,” “an,” and “the,” include plural referents unlessexpressly and unequivocally limited to one referent. For example,reference to “a compartment” includes one, two, three or morecompartments.

Bioactive Agent or Bioactive Compound, as used herein, refers to acompound or entity that alters, inhibits, activates, or otherwiseaffects biological or chemical events. For example, bioactive agents mayinclude, but are not limited to, osteogenic or chondrogenic proteins orpeptides, anti-AIDS substances, anti-cancer substances, antibiotics,immunosuppressants, anti-viral substances, enzyme inhibitors, hormones,neurotoxins, opioids, hypnotics, anti-histamines, lubricants,tranquilizers, anti-convulsants, muscle relaxants and anti-Parkinsonsubstances, anti-spasmodics and muscle contractants including channelblockers, miotics and anti-cholinergics, anti-glaucoma compounds,anti-parasite and/or anti-protozoal compounds, modulators ofcell-extracellular matrix interactions including cell growth inhibitorsand antiadhesion molecules, vasodilating agents, inhibitors of DNA, RNAor protein synthesis, anti-hypertensives, analgesics, anti-pyretics,steroidal and non-steroidal anti-inflammatory agents, anti-angiogenicfactors, angiogenic factors, anti-secretory factors, anticoagulantsand/or antithrombotic agents, local anesthetics, ophthalmics,prostaglandins, anti-depressants, anti-psychotic substances,anti-emetics, and imaging agents. In certain embodiments, the bioactiveagent is a drug. In some embodiments, the bioactive agent is a growthfactor, cytokine, extracellular matrix molecule or a fragment orderivative thereof, for example, a cell attachment sequence such as RGD.A more complete listing of bioactive agents and specific drugs suitablefor use in the present invention may be found in “PharmaceuticalSubstances: Syntheses, Patents, Applications” by Axel Kleemann andJurgen Engel, Thieme Medical Publishing, 1999; the “Merck Index: AnEncyclopedia of Chemicals, Drugs, and Biologicals”, Edited by SusanBudavari et al., CRC Press, 1996; and the United StatesPharmacopeia-25/National Formulary-20, published by the United StatesPharmcopeia Convention, Inc., Rockville Md., 2001, each of which isincorporated herein by reference.

Biocompatible, as used herein, refers to materials that, uponadministration in vivo, do not induce undesirable long-term effects.

Bone, as used herein, refers to bone that is cortical, cancellous orcortico-cancellous of autogenous, allogenic, xenogenic, or transgenicorigin.

Demineralized, as used herein, refers to any material generated byremoving mineral material from tissue, e.g., bone tissue. In certainembodiments, the demineralized compositions described herein includepreparations containing less than 5% calcium and preferably less than 1%calcium by weight. Partially demineralized bone (e.g., preparations withgreater than 5% calcium by weight but containing less than 100% of theoriginal starting amount of calcium) is also considered within the scopeof the invention. In some embodiments, demineralized bone has less than95% of its original mineral content. Demineralized is intended toencompass such expressions as “substantially demineralized,” “partiallydemineralized,” and “fully demineralized.”

Demineralized bone matrix, as used herein, refers to any materialgenerated by removing mineral material from bone tissue. In preferredembodiments, the DBM compositions as used herein include preparationscontaining less than 5% calcium and preferably less than 1% calcium byweight. Partially demineralized bone (e.g., preparations with greaterthan 5% calcium by weight but containing less than 100% of the originalstarting amount of calcium) are also considered within the scope of theinvention.

Osteoconductive, as used herein, refers to the ability of anon-osteoinductive substance to serve as a suitable template orsubstance along which bone may grow.

Osteogenic, as used herein, refers to the ability of an agent, material,or implant to enhance or accelerate the growth of new bone tissue by oneor more mechanisms such as osteogenesis, osteoconduction, and/orosteoinduction.

Osteoimplant, as used herein, refers to any bone-derived implantprepared in accordance with the embodiments of this invention andtherefore is intended to include expressions such as bone membrane, bonegraft, etc.

Osteoinductive, as used herein, refers to the quality of being able torecruit cells from the host that have the potential to stimulate newbone formation. Any material that can induce the formation of ectopicbone in the soft tissue of an animal is considered osteoinductive. Forexample, most osteoinductive materials induce bone formation in athymicrats when assayed according to the method of Edwards et al.,“Osteoinduction of Human Demineralized Bone: Characterization in a RatModel,” Clinical Orthopaedics & Rel. Res., 357:219-228, December 1998,incorporated herein by reference.

Superficially demineralized, as used herein, refers to bone-derivedelements possessing at least about 90 weight percent of their originalinorganic mineral content, the expression “partially demineralized” asused herein refers to bone-derived elements possessing from about 8 toabout 90 weight percent of their original inorganic mineral content andthe expression “fully demineralized” as used herein refers to bonecontaining less than 8% of its original mineral context.

I. Introduction

A delivery system for delivering a substance or material to a surgicalsite is provided. In various embodiments, the delivery system comprisesa covering and a substance for delivery by the covering. The coveringprovides a superior containment of the substance, such as graftmaterial, which helps focus and concentrate materials that providehealing at the surgical site. In some embodiments, the covering alsohelps the surgeon perform less invasive procedures, by delivering acontained unit of grafting material to the surgical site.

The delivery system may be used to treat a wide variety of bone or softtissue defects including surgically created or pre-existing (such as bytrauma) defects. In some embodiments, the delivery system may be used totreat contained bony voids or contained defects. Such bony voids arevoids or cavities that have a cortical shell on three sides. In someembodiments, the delivery system may be used to treat critical defects.Generally, critical defects are defects that will not heal spontaneouslyand must be grafted in order to assure healing. In some embodiments, thedelivery system may be used to treat segmental defects. Segmentaldefects are defects in the cortical shaft of a long bone in which asegment is missing. In some embodiments, the delivery system may be usedto treat contained or non-critical defects wherein the delivery systemmay act as a plug to assist healing. Other applications for the deliverysystem are discussed herein and none are intended to be limiting.

The delivery system comprises a covering and a substance wherein thesubstance is provided within the covering for delivery to the surgicalsite. The delivery system provides increased handling properties,ability to place grafting material reliably using minimally invasiveprocedures, and improved delivery characteristics such as graftretention compared with other systems. In some embodiments, uponplacement, the covering facilitates transfer of the substance and/ormaterials to the surgical site. In some embodiments, for example whereinthe covering holds graft materials, the covering substantially preventsgraft migration. The covering may participate in, control, or otherwiseadjust, the release of the substance from the covering or penetration ofthe covering by surrounding materials, such as cells or tissues.

Generally, the covering may be a single or multi-compartment structurecapable of at least partially retaining a substance provided thereinuntil the covering is placed at a surgical site. In some embodiments,the covering may be substantially non-expandable or minimallydeformable. In some embodiments, the covering may be a temporarycovering wherein the covering is substantially resorbable. For example,in some embodiments, the covering may be formed of a material that issubstantially resorbed within 2 weeks, within 4 weeks, within 12 weeks,or within other suitable time frame. Accordingly, in some embodiments adelivery system including the covering may be a temporary deliverysystem. The covering may include one or more attachment mechanisms forretaining the covering at the surgical site. The attachment mechanismmay be a mechanical attachment mechanism, a physical attachmentmechanism, a biological attachment mechanism or a chemical attachmentmechanism, or may employ combinations of these. The attachment mechanismmay be used to attach the covering to skeletal or soft tissue proximatethe surgical site.

In some embodiments, the covering may be used for containment ofparticulate or morselized materials (the substance provided in thecovering), optionally to provide a focus or concentration of biologicalactivity. In some embodiments, the covering may be used for containmentof a substance one or more of bone particles, bone fibers, otherosteoinductive or osteoconductive materials, BMP, antibiotics, or othermaterials.

In some embodiments, the covering may be used for maintaining materials(the substance provided in the covering) in spatial proximity to oneanother, possibly to provide a synergistic effect. In some embodiments,the covering may be used to control availability of a substancesprovided within the covering to cells and tissues of a surgical siteover time. In some embodiments, the covering may be used for deliverythrough a limited opening, such as in minimally invasive surgery ormini-open access. In some embodiments, the covering may be used todeliver morselized or particulated materials (the substance provided inthe covering) in pre-measured amounts. In other embodiments, thesubstance may be liquid or flowable, or combinations of these withparticulate, morselized, and/or other materials.

In various embodiments, the covering may contain a substance or materialsuch as a graft material. The covering limits, and in some embodimentseliminates, graft migration and maintains graft density. The deliverysystem, with contained substance or material, may be configured toconform to surrounding bony contours or implant space. In someembodiments, the delivery system provides a pathway for healing/cellpenetration and tissue ingrowth. Thus, the covering may facilitatetransfer or diffusion of materials into and out of the covering. Forexample, the covering may facilitate diffusion from the covering of asubstance provided within the covering or may facilitate diffusion intothe covering of materials in the surgical site, such as cells andtissues, into the covering. The covering may be configured to permitdiffusion of some materials while substantially preventing diffusion ofother materials. Further, in various embodiments, the covering may beconfigured such that diffusion is permitted into or out of certainportions of the covering but not other portions of the covering. In someembodiments, the covering may merely retain a substance at the surgicalsite.

II. Covering Material

The covering may comprise a structural material and, in someembodiments, a functional material. The structural material may comprisea mesh material, a polymeric material, a substantially or other. Thefunctional material may comprise, for example, a radiopaque material, abacteriocidal material, or other.

Structural Material Characteristics

In various embodiments, in accordance with the specific application forwhich the covering is being used, the covering may be flexible, may benon-elastic, or may be elastic. The covering material may be braided,woven, non-woven shape memory, particulate, threaded, porous,non-porous, or substantially solid. While the term “structural” is usedto describe the material forming the main structure of the covering, itis to be appreciated that this is not intended to imply that thecovering need have structural or load-bearing characteristics.

The covering may participate in, control, facilitate, prevent, orotherwise adjust the release of the substance. For example, the coveringmay act as a selectively permeable membrane and/or may be porous, withthe level of porosity being related to the nature of the substancesinside the covering. Thus, the material for and configuration of thecovering may be selected or adjusted based on desired releasecharacteristics. Specific properties of the structural material that maybe adjusted include thickness, permeability, porosity, strength,flexibility, elasticity, and others. It is to be appreciated that someof these properties may depend on others. For example, the thickness andporosity of the material may contribute to its strength, flexibility,and elasticity. In some embodiments, the covering may be made of asquishy, moldable, sticky, and/or tacky material to facilitate placementand packing of the covering.

In some embodiments, the covering may be porous to fluid and/or cells,may be biocompatible, and may be resistant to rupture (including shouldthe substance provided therein swell). In some embodiments, the coveringwith the substance provided therein may be load-bearing. The coveringmay be resorbable or non-resorbable. The covering may provide increasedhandling properties, may have irrigation resistance, may have materialretention characteristics, and/or may support cellular penetration.Flexibility of the covering may be selected to suit particularapplications. In some applications, it may be desirable to have aflexible covering.

If the covering is made from a resorbable material, the coveringdegrades and disappears after a period of time. The covering thus may beconsidered a temporary covering. If the covering is not made of aresorbable material, the covering remains in the body. Tissue ingrowthmay occur to bind the host tissue to the substance provided within thecovering. Tissue ingrowth through and around the covering, between thehost tissue and the substance provided within the covering, may bepromoted via openings in the covering.

In various embodiments, the covering may comprise a porous material or amesh material. The size of the pores of the covering may be designed topermit cellular infiltration (approximately several microns to severalmillimeters), but may also be designed specifically to exclude cellsfrom the inside of the covering (e.g. approximately 0.45 microns) andonly allow diffusion of small molecules (proteins and hormones). Thus,the covering may act to control access to the interior of the deliverysystem by cells. U.S. Patent Application Publication No. 2005/0283255for Tissue-Derived Mesh for Orthopedic Regeneration describes suitablemanners for forming a mesh for use with a covering as provided hereinand is herein incorporated by reference in its entirety.

The covering may be formed of a resorbable or nonresorbable, natural orsynthetic, biocompatible material. In some embodiments, more than onematerial may be used, including as multiple layers. For example, in anembodiment comprising two compartments, one or more materials may beused for the first compartment and a different material or materials maybe used for the second compartment. For example, one compartment orportions thereof may be made of material or materials that provide adesired property or properties relative to other compartments orportions thereof, such as increased or decreased resorbability orstiffness, or the different compartments or portions thereof may beimparted with different drug delivery properties. Alternatively, allcompartments may comprise the same material or mixtures of materials.Where the characteristics of the material are varied betweencompartments or over the surface of a single compartment, the pores ofthe first compartment or portion thereof may be larger than the pores ofthe second compartment.

The covering may comprise any suitable structure for delivering asubstance in vivo. Thus, as described, the covering may comprise a mesh.In other embodiments, the covering may comprise a polymeric structurewith a chamber provided therein. The chamber may be filled with asubstance for delivering in vivo, such as autograft, demineralized bonematrix, or others disclosed herein.

In embodiments comprising more than one compartment, characteristics ofthe covering material may be varied between compartments. Generally, theporosity, flexibility, strength, or any other characteristic of onecompartment may vary from that characteristic of the other compartment.Further, characteristics of the covering may vary at different positionsof the covering regardless of compartmental configuration of thecovering.

In some embodiments, the covering may expand when placed in the body.Expansion can be provided in at least two ways: the covering may becompressed such that the covering expands when placed in the body or thecovering may be made of a material that expands when it comes in contactwith water or other bodily fluids, either by way of liquid absorption,or by stretching when the materials inside it absorb liquid andthemselves expand. In some embodiments, the covering may comprise ashape memory material such as copper-zinc aluminum-nickel alloy,copper-aluminum-nickel alloy, and nickel-titanium (NiTi) alloy.Reinforcing materials such as cortical bone, calcium phosphates, etc.may be incorporated into the structure of the covering to reinforce it.In other embodiments, the covering may be substantially non-expandableor minimally deformable.

The covering may be configured for specific compressive strength andrigidity by adjusting density and resorption time of the covering. Insome embodiments, a coating may be provided over the covering. Forexample, the coating may be a compound of poly-L-lactide, ofpolyglycolic acid, or their polymers, or polyhydroxyalkanoates(polyhydroxybutyrates and polyhydroxyvalerates and copolymers). Thecoating may be selected such that it has a resorption time wherein it isresorbed by the body and the material within the covering is permittedto exit through openings in the covering.

Exemplary Covering Materials

Polymeric material (for example, see U.S. Pat. Nos. 6,696,073,6,478,825, 6,440,444, and 6,294,187, 7,985,414 and U.S. PatentPublication No. and 2005/0251267, all herein incorporated by referencein their entirety); woven material and braided material (for example,see U.S. Patent Publication No. 2005/0283255, herein incorporated byreference in its entirety); non-woven materials; shape memory material;porous materials; and non-porous materials may be used. In someembodiments, outer particles may be used to contain inner particles;particles may be attached to threads of material, and/or porosity may beadded to mesh fibers. In some embodiments, materials may be used forportions of the covering, such as for a compartment of the covering,that are substantially impenetrable.

In some embodiments, the covering may comprise a mesh material. Suitablemesh materials include natural materials, synthetic polymeric resorbablematerials, synthetic polymeric non-resorbable materials, and othermaterials. Natural mesh materials include silk, extracellular matrix(such as DBM, collagen, ligament, tendon tissue, or other),silk-elastin, elastin, collagen, and cellulose. Synthetic polymericresorbable materials include poly(lactic acid) (PLA), poly(glycolicacid) (PGA), poly(lactic acid-glycolic acid) (PLGA), polydioxanone, PVA,polyurethanes, polycarbonates, polyhydroxyalkanoates(polyhydroxybutyrates and polyhydroxyvalerates and copolymers),polysaccharides, polyhydroxyalkanoates polyglycolide-co-caprolactone,polyethylene oxide, polypropylene oxide, polyglycolide-co-trimethylenecarbonate, poly(lactic-co-glycolic acid), and others. See Chen and Wu,“The Application of Tissue Engineering Materials,” Biomaterials, 2005,26(33): p. 6565-78, herein incorporated by reference in its entirety.Other suitable materials include carbon fiber, metal fiber,polyertheretherketones, non-resorbable polyurethanes, polyethers of alltypes, polyethylene terephthalate, polyethylene, polypropylene, Teflon,and various other meshes. In other embodiments, the covering maycomprise non-woven material such as spun cocoon or shape memorymaterials having a coil shape or shape memory alloys. Alternatively, anyof these materials may be used in a non-mesh form.

Generally, the covering may be formed of any natural or syntheticstructure (tissue, protein, carbohydrate) that can be used to form acovering configuration. Thus, the covering may be formed of a polymer(such as polyalkylenes, for example, polyethylenes, polypropylenes),polyamides, polyesters, poly(glaxanone), poly(orthoesters),poly(pyrolicacid), poly(phosphazenes), polycarbonate, otherbioabsorbable polymer such as Dacron or other known surgical plastics, anatural biologically derived material such as collagen, gelatin,chitosan, alginate, a ceramic (with bone-growth enhancers,hydroxyapatite), PEEK (polyetheretherketone), dessicated biodegradablematerial, metal, composite materials, a biocompatible textile (forexample, cotton, silk, linen), extracellular matrix components, tissues,or composites of synthetic and natural materials, or other. Variouscollagen materials can be used, alone or in combination with othermaterials, including collagen sutures and threads. Some examples includepolymer or collagen threads woven, or knitted, into a mesh. Othersuitable materials include thin polymer sheets molded in the presence ofa porogen and having underwent leaching; polymer sheets or naturallyderived sheets such as fascia and other collagen materials, smallintestinal submucosa, or urinary bladder epithelium, the sheets beingpunctured to introduce porosity; specific shapes printed using availableor future printing technologies; naturally secreted materials such asbacterial cellulose grown within specific molds.

In some embodiments, mesh fibers may be treated to impart porosity tothe fibers. This may be done, for example, to PLA, PLGA, PGA, and otherfibers. One suitable method for treating the mesh fibers comprisessupercritical carbon dioxide treatment to partially solubilize theparticles. This treatment may further be carried out for viralinactivation. Another suitable method for treating the mesh fiberscomprises explosive decompression. Explosive decompression generatesporosity and leads to controlled permeability. The mesh material furthermay be loaded with cells, growth factors, or bioactive agents.

In further embodiments, fibers of a mesh material may be treated such asby having particles adhered thereto. The particles may be, for example,bone particles. Thus, in one embodiment, the covering may comprise aplurality of threads formed into a fabric. The threads may haveparticles adhered thereto. For example, the threads may have particlesstrung on the thread. In an alternative embodiment, the covering may beformed of a material and the material may be coated with particles.

In yet other embodiments, the covering may comprise a non-porousmaterial, which may be permeable. A non-porous material may be used forlater (or delayed) delivery of a substance provided therein. Suchsubstance may comprise, for example, cells, growth factors, or bonemorphogenetic proteins. Accordingly, in one embodiment, a deliverysystem for delayed delivery of cells, growth factors, or bonemorphogenetic proteins is provided comprising a non-porous covering.

In particular, in various embodiments, the device may comprise abioerodible, a bioabsorbable, and/or a biodegradable biopolymer that mayprovide immediate release, or sustained release of the clonidine.Examples of suitable sustained release biopolymers include but are notlimited to poly (alpha-hydroxy acids), poly (lactide-co-glycolide)(PLGA), polylactide (PLA), polyglycolide (PG), polyethylene glycol (PEG)conjugates of poly (alpha-hydroxy acids), poly(orthoester)s (POE),polyaspirins, polyphosphagenes, collagen, starch, pre-gelatinizedstarch, hyaluronic acid, chitosans, gelatin, alginates, albumin, fibrin,vitamin E compounds, such as alpha tocopheryl acetate, d-alphatocopheryl succinate, D,L-lactide, or L-lactide, ,-caprolactone,dextrans, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA,PEGT-PBT copolymer (polyactive), PEO-PPO-PAA copolymers, PLGA-PEO-PLGA,PEG-PLG, PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymers, SAIB(sucrose acetate isobutyrate) or combinations thereof. As persons ofordinary skill are aware, mPEG and/or PEG may be used as a plasticizerfor PLGA, but other polymers/excipients may be used to achieve the sameeffect. mPEG imparts malleability to the resulting formulations. In someembodiments, these biopolymers may also be coated on the medical deviceto provide the desired release profile. In some embodiments, the coatingthickness may be thin, for example, from about 5, 10, 15, 20, 25, 30,35, 40, 45 or 50 microns to thicker coatings 60, 65, 70, 75, 80, 85, 90,95, 100 microns to delay release of the substance from the medicaldevice. In some embodiments, the range of the coating on the medicaldevice ranges from about 5 microns to about 250 microns or 5 microns toabout 200 microns to delay release from the medical device.

In various embodiments, the medical device comprisespoly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide(PGA), D-lactide, D,L-lactide, L-lactide, D,L-lactide-co-ε-caprolactone,D,L-lactide-co-glycolide-co-ε-caprolactone, L-lactide-co-ε-caprolactoneor a combination thereof.

While certain embodiments are described with respect to having meshcharacteristics, it is to be appreciated that not all embodiments mayhave such mesh characteristics. Further, the material used for thecovering and its characteristics may be selected for specificapplications. For example, in some embodiments, the covering may beformed of a resorbable material, such as formed as a resorbablecontainer or capsule. Such resorbable material may be useful indelivering, for example, antibiotic to a site by an outer resorbablematerial, and then gradually exposing inner graft material after theinfection is cleared. In such embodiments, the delivery system comprisesa temporary delivery system.

Functional Material Characteristics

The covering material may have functional characteristics.Alternatively, other materials having functional characteristics may beincorporated into the covering. Functional characteristics may includeradiopacity, bacteriocidity, source for released materials, tackiness.Such characteristics may be imparted substantially throughout thecovering or at only certain positions or portions of the covering.

Suitable radiopaque materials include, for example, ceramics,mineralized bone, ceramics/calcium phosphates/calcium sulfates, metalparticles, fibers, iodinated polymer or mixtures thereof. Othertechniques for incorporating a biocompatible metal or metal salt into apolymer to increase radiopacity of the polymer may also be used.Suitable bacteriocidal materials may include, for example, tracemetallic elements. In some embodiments, trace metallic elements may alsoencourage bone growth.

Functional material, such as radiopaque markers, may be provided at oneor more locations on the covering or may be provided substantiallythroughout the covering. Thus, for example, in a tubular covering, aradiopaque marker may be provided at a tip of the tubular covering. Suchmarker may facilitate placement of the covering. Radiopaque materialsmay be incorporated into the covering and/or into the substance fordelivery by the covering. Further, radiopaque materials may be providedat only some locations on the covering such that visualization of thoselocations provides indication of the orientation of the covering invivo.

The covering itself may be designed to release materials duringdegradation of the covering material. Thus, bone morphogenic proteins(BMPs), growth factors, antibiotics, angiogenesis promoting materials(discussed more fully below), bioactive agents (discussed more fullybelow), or other actively releasing materials may be incorporated intothe covering material such that as the covering material is degraded inthe body, the actively releasing material is released. For example, anactively releasing material may be incorporated into a biodegradablepolymer covering such as one manufactured of a biodegradable polyestersuch as poly(lactic acid) (PLA), poly(glycolic acid) (PGA),poly(lactic-co-glycolic acid) (PLGA), or polyhydroxyalkanoates(polyhydroxybutyrates and polyhydroxyvalerates and copolymers). In someembodiments, poly(ethylene glycol) (PEG) may be incorporated into thebiodegradable polyester to add hydrophilic and other physico-chemicalproperties to enhance drug delivery. In some embodiments, composites ofallograft bone and biodegradable polymers (for example, PLEXUR™ productsavailable from Osteotech) may be used in the covering.

In some embodiments, the covering may comprise a material that becomestacky upon wetting. Such material may be, for example, a protein orgelatin based material. Tissue adhesives, including mussel adhesiveproteins and cryanocrylates, may be used to impart tackiness to thecovering. In further examples, alginate or chitosan material may be usedto impart tackiness to the covering. In further embodiments, an adhesivesubstance or material may be placed on a portion of the covering or in aparticular region of the covering to anchor that portion or region ofthe covering in place at an implant site.

In one embodiment of a covering comprising two compartments, first andsecond materials may be used for the first and second compartments,respectively. The first material may release or expose a growth factoraccording to a first rate and the second material may release a growthfactor according to a second rate. Further, the growth factors releasedby the first and second compartments may be the same or may bedifferent. For example, an angiogenic growth factor may be provided withthe first compartment and an osteoinductive growth factor may beprovided with the second compartment.

Mesh Formulation

Any suitable technique may be used for forming a material for thecovering. Generally, the material may be formed as a sheet, as a mesh,or in other configuration. In some embodiments, the material may be atextile type material. Thus, for example, the material may be formedusing a textile approach such as be weaving, rug making, knitting. Suchformation may be by a mechanical or industrial method. In anotherembodiment, a substantially solid sheet may be formed and may be treatedto assume a configuration penetrable by cells, fluids, and proteins. Forexample, the sheet may be perforated, may be expanded to createopenings, or other. Also, it would be perfectly suitable to take a thinsheet of the covering material, and to perforate it, expand it to createopenings, or otherwise make it penetrable by cells, fluids and proteins.

In one embodiment, elongated bone-derived particles or fragments ofsmall intestinal submucosa may be combined longitudinally into threesmall bundles, each having, for example, from about 1 to about 3 tissueparticles. The three bundles may then be braided. Various methods ofbraiding and types of braids any of which may be useful in producing thematerial of the invention herein are also useful in the delivery systemsof this application. The ends of the braided tissue-derived particlesmay then be glued together using a fixation agent to prevent theirunraveling, or they may be held together with a biocompatible polymer ormetal band.

In an alternative embodiment, bone-derived particles are combined with asolvent to form a material. Exemplary solvents include water, loweralkanols, ketones, and ethers and mixtures of any of these or othermaterials. The material may then be extruded at an appropriatetemperature and pressure to create a thread. Threads may also beproduced by spinning, drawing, rolling, solvent-extruding, cutting orlaser cutting from a sheet or bar stock. The material may alternativelybe cast or molded into a solid sheet or bar stock and then cut into thinthreads. These may be used immediately or woven into a mesh.Alternatively or in addition, they may be spliced, wrapped, plied,cabled, braided, woven, or some combination of these. The material maybe shaped by thermal or chemical bonding, or both. In one embodiment, aportion of the solvent is removed from the material before extrusion.

Alternatively or in addition, the material may be cast as a slurry,extruded, or molded. A variety of materials processing methods will bewell known to those skilled in the art. For example, the material may besolvent cast using a press such as a Carver press to spread the materialinto a film. Solvent evaporation will yield a porous film.Alternatively, the material may be compression molded into a film. Themesh size or porosity of the film will depend on the thickness of thefilm and the viscosity of the precursor and can be easily manipulated byone skilled in the art. Where elongated particles are used in anextruded aggregate, they will tend to be aligned roughly parallel to oneanother.

In an alternative embodiment, a thread of a biocompatible natural orsynthetic material, for example, polylactide or collagen, may be coatedwith tissue-derived or other elements, for example, by dubbing. Forexample, a polymer fiber may be coated with an adhesive, for example,lecithin, and bone particles or other osteoconductive or osteoinductivefibrils allowed to adhere to the thread. The thread may then be twistedon itself or with a second or a plurality of similarly treated threads.Alternatively or in addition, the threads may be braided. The adhesivemay be a lipid that is waxy at room temperature, for example, a di- ortri-glyceride that is solid at room temperature. Alternatively or inaddition, the adhesive may be a phosphocholine or phosphatidylcholine.In some embodiments, the adhesive is a material that binds both thethread and the material that is used to coat the thread (e.g., boneparticles) but that does not degrade either. Non-aqueous adhesives mayimprove the stability of the final aggregate as compared to aqueousadhesives.

Suitable fibers may be formed utilizing well known techniques, includingbraiding, plying, knitting, weaving, felting, that are applied toprocessing natural fibers, for example, cotton, silk, and syntheticfibers made from synthetic bioabsorbable polymers, such aspoly(glycolide) and poly(lactic acid), nylon, cellulose acetate. In someembodiments, collagen thread is wound onto cylindrical stainless steelspools. The spools are then mounted onto the braiding carousel, and thecollagen thread is then assembled in accordance with the instructionsprovided with the braiding machine. In one particular run, a braid wasprepared of four collagen threads, which consisted of two threads ofnon-crosslinked collagen and two threads of crosslinked collagen. Oneskilled in the art will recognize that these techniques may be appliedto the other fibrous materials described herein.

Fibers and more evenly dimensioned particles may also be plied intoyarns using the same methods and same machinery known to those skilledin the art in plying threads made out of other material, such as cotton,polyester. Four collagen threads were twisted together. Three of theresultant 4-ply strands were then twisted together in the oppositedirection, and then 5 of the resultant 12 ply strands were twisted inthe opposite direction.

Elongated materials including multistranded materials, for examplebraids, plied yarns, cables, may be knitted into tubular or flat fabricsby using techniques known to those skilled in the art of producingfabrics manufactured from other types of threads. Various biologicallyactive substances can be incorporated in, or associated with, thebraided, knitted, or woven materials. Particles and fibers and materialsof these (including multistranded materials) may alternatively oradditionally be assembled into a material by non-woven methods such aslaying, needle-punching, and hooking (as for a rug). For example, athread may be attached to another thread or a pressed film.

Regardless of the assembly method, the material shape, mesh size, cablethickness, and other structural characteristics, such as architecture,may be customized for the desired application. For example, where a twodimensional aggregate is used to retain a thixotropic material within agap, a tight weave is preferred to prevent leakage. To optimize cell orfluid migration through the mesh, the pore size may be optimized for theviscosity and surface tension of the fluid or the size of the cells. Forexample, pore sizes on the order of approximately 100-200 μm may be usedif cells are to migrate through the mesh. Mesh size may be controlled byphysically weaving strands of the material by controlling the ratio ofsolvent to solids in a precursor material.

Cells may be seeded onto the material, or contained within it. In oneembodiment, cells may be encapsulated in a matrix such as alginate orcollagen gel and the capsules placed on the material. Seeded materialsgenerally do not need to be incubated for long periods of time insolutions that could partially dissolve the binding agent. Instead, thecapsules may be placed on the material or covering shortly beforeimplantation. In another embodiment, cells are simply mixed with a gelwhich is then combined with the material. Alternatively, a material orcovering may be cultured with cells before implantation. In oneembodiment, thicker materials are used for culturing to increasemechanical integrity during implantation. Any class of cells, includingconnective tissue cells, organ cells, muscle cells, nerve cells, andstem cells, may be seeded onto the implant. In an exemplary embodiment,connective tissue cells such as osteoblasts, osteoclasts, fibroblasts,tenocytes, chondrocytes, and ligament cells and partially differentiatedstem cells such as mesenchymal stem cells and bone marrow stromal cellsare employed.

III. Covering Configuration or Form

The shape, configuration, or form of the covering may be selected forparticular applications. Such shape and configuration may include, forexample, the basic shape of the covering (for example, a cylinder or abag), whether the covering has a single or a plurality of compartments,and whether the covering includes attachment mechanisms. The covering(or delivery system) may be configured to conform to surrounding bonycontours of the space in which it is placed.

Form

In various embodiments, the covering may be formed of as a mesh and maycomprise a woven material. The woven material may have varying degreesof permeability. It may be permeable, semi-permeable, or non-permeable.Permeability may be with respect to cells, to liquids, to proteins, togrowth factors, to bone morphogenetic proteins, or other. In furtherembodiments, the material may be braided.

In alternative embodiments, the covering may comprise a substantiallysolid structure, such as a polymer structure with a chamber, or a spuncocoon.

Shape

The covering may have any suitable configuration. For example, thecovering may be formed as a ring, a cylinder, a cage, a rectangularshape, a mesh, a suture-like wrap, a continuous tube, or otherconfiguration. In specific embodiments, the covering may be formed as athin tube designed to be inserted through catheters or an introducertube, a rectangular shape designed to fit adjacent to spinal processesfor posterolateral spine fusion, a cube like structure designed to fitbetween vertebral bodies or within cages for interbody spinal fusion, atube-like shape where the ends are designed to be fitted onto nonunionlong bone defects, relatively flat shapes designed to fill cranial ormaxillofacial defects, rectangular structures designed for osteochondraldefects, structures pre-shaped to fit around various implants (forexample, dental, doughnut with hole for dental implants), or relativelyelastic ring-like structures that will stretch and then conform toshapes (for example, rubber band fitted around processes). In anembodiment wherein the covering is formed as a cage, the cage maycomprise a plurality of crossed filaments which define between them aseries of openings for tissue ingrowth. Any of these shapes may be usedfor a covering comprising a plurality of compartments. For example, in atubular embodiment, the tube may be formed into a plurality ofcompartments by tying a cord around the tube at one or more points, orby other suitable mechanism such as crimping, twisting, knotting,stapling, sewing, or other. The configuration of the covering may bedetermined by the substance to be provided within the covering. Forexample, if the substance to be contained comprises fibers, the coveringmay be formed as strings or sutures that are wrapped around the fibers.

Compartments

Single Compartment

An osteogenic material delivery system 100 in accordance with oneembodiment is depicted in FIG. 1. As shown in FIG. 1, delivery system100 comprises a single compartment covering 102 having an elongatedcontainment 104 for housing a substance for delivery to a surgical site.Elongated containment portion 104 has a first and second end 106, 108.As further illustrated in FIG. 1, first end 106 is open and configuredto receive autograft or allograft; second end 108 is sealed andcomprises mesh or other sealable material.

Elongated containment portion 104 comprises a length, width and crosssection which may vary depending on the application for the covering.The cross section can be tubular or cylindrical and in alternativeembodiments, any cross-sectional shape, such as a generally circular,oval, rectangular, generally square, or any other suitable shape may beused.

In other embodiments as shown in FIGS. 1 to 6, coverings 102, 202, 302,402, 502 and 602 comprise a mesh material and the delivery system can bea mesh bag. Within these coverings or mesh bags, there is provided aparticulated substance such as milled bone or DBM particles/fibers,wherein the ratio of DBM fibers to DBM chips is about 30:70.

In various embodiments, the covering may be configured to facilitateplacement of graft material in the covering. For example, in theembodiments illustrated in FIGS. 1 to 8, the delivery systems alsocomprise a closing member, which can be drawing strings, stitches,sutures, heat seals, adhesion, pressure fittings, coil ring, twist tieor combinations thereof. As illustrated in FIG. 1, closing member 110can be a suture located proximate open end 106 of container 104.

In other embodiments, as illustrated in FIG. 2, closing member 210 canbe slidably adjusted over the length of container 204 or can be attachedafter a portion of container 204 has been filled with bone materialeither prior to or during a surgical procedure. In FIG. 2, closingmember 210 can incorporate a geometric ring providing a stiffeningdesign so that container or pouch 204 can remain in an open position forfilling. On filling, the surgeon can twist the upper portion of pouch204 and fold it over the lower portion, a maneuver facilitated by theclosing ring such that the pouch is closed without the need foradditional suturing.

As further illustrated in the embodiments of FIGS. 2 and 3, in someembodiments, closing members 210 or 310 define upper portions 206, 306and lower portions 208, 308 of containers 204 or 304, respectively. Uponclosing lower portion 208, 308, with closing members 210, 310, upperportions 206, 306 can be folded over lower portions 208, 308 and,thereafter inserted at a desired surgical site. In other embodiments,the closing member can be omitted and upper portions 206, 306 can betwisted at a selected location and then folded over lower portions 208,308 of containers 204 or 304, respectively.

In other embodiments illustrated in FIGS. 4 to 6, coverings 402, 502 and602 can be closed with closing members comprising drawstrings 410, 510or 610 located proximate openings 412, 512, about a midway location 614as illustrated in FIG. 6 or at any desirable location along theelongated containment. In the embodiment illustrated in FIG. 6, uponclosing with drawstring 610, upper portion 606 can fold over lowerportion 608 of containment 604 as more specifically illustrated in FIG.3.

In various embodiments, as illustrated in FIG. 7, in an embodiment ofthis disclosure, drawstrings 714 are positioned around the perimeter ofcovering 702 proximate opening 712 of covering 702 slidably received incasing or sleeve 770 so that when the end portions of the drawstring 714are pulled out of the drawstring casing 770 through the two apertures772, 774, the periphery of covering 702 gathers adjacent the casing topermit the periphery of covering 702 to reduce in size sufficiently toenclose the autograft chips or other graft material therein.

In another embodiment, as illustrated in FIG. 8, drawstring 814 can becontinuous, slidably received in casing 870 and has two loops 880, 882which extend as oppositely disposed segments around the outsideperimeter of the covering 802 at apertures 872, 874 of casing 870. Uponpulling loops 880 and 882, drawstring 814 gathers the periphery ofcovering 802 adjacent casing 870 to permit the periphery of covering 802to reduce in size sufficiently to enclose the autograft chips or othergraft material therein.

In various other embodiments, the drawstrings used to close the openingof the covering can be wires made of nitinol or any other shape memoryalloy. For example, nitinol wires can be slidably received in the casingaround the perimeter of the opening of the cover and upon closing thenitinol wires would relapse to a closed position thereby securing theallograft chips or other graft material inside the covering.

With further reference to FIG. 1, one or both ends 106, 108 of elongatedcontainment 104 may contain an attachment or coupling mechanism (notshown) to attach the covering to skeletal or soft tissue proximate to asurgical site. Any suitable attachment mechanism can be used, such as atab, loop, tack or other structure adapted for attachment at the site.Also, for example, a covering may include a hook-and-eye (Velcro)portion.

In certain other embodiments only one end 108 of the covering or meshbag 102 is sealed while the other is open to provide easy access formixing DBM particles/fibers with autologous milled bone or growth factorbefore or during the surgical procedure. Subsequently, the covering ormesh bag can be closed by various mechanisms including draw strings asshown in FIGS. 4 and 5, sutured or heat seal closed. The draw string canbe sequentially or diagonally stitched or in any other patternconfigured to close the mesh bag after all the materials were added andprior to placing at a surgical site.

Closing Mechanism

In various embodiments closing mechanisms useful for the deliverysystems described herein comprise drawing strings, stitches, sutures,wing sutures, heat seals, adhesion, pressure fittings, coil ring, twisttie or combinations thereof. Closing mechanisms comprise a materialselected from bioerodible polymers, bioabsorbable polymers,biodegradable biopolymers, synthetic polymers, copolymers orcombinations thereof. In some embodiments, sutures useful as closingmember for the delivery system described herein include absorbables andnon-adsorbable sutures. Absorbable sutures comprises polyglycolic acid,polylactic acid, and polydioxanone, and caprolactone. Non-absorbablessutures include sutures made of nylon and polypropylene. Coil rings canbe made of surgical stainless steel or nitinol material, which uponclosing can relapse to a closed position.

Attachment Mechanisms

Generally, any combination of mechanical, physical, chemical, orbiological attachment mechanisms may be used. The covering may beconfigured with structures to permit attachment at the surgical site,such as to skeletal tissue or to soft tissue structures, or forattachment to other coverings, or for attachment to adjacent implantablemedical devices or products (such as a rod or screw or cross-brace of apedicle screw fixation system, a hip prosthesis, a bone plate, and thelike). Generally, the attachment mechanism may be used to retain thecovering at the surgical site and any mechanisms capable of doing so maybe used. The attachment may be to bone or to adjacent tissues such asmuscle, tendon, or ligament. Where the covering retains a bone graftsubstance, the covering may be held in a relatively stable positionrelative to bone (or relative to the surgical site or surgical defect)to promote bone growth. Accordingly, in some embodiments, the deliverysystem may be suitable for assisting in attaching tendons, artificialtendons, or ligaments to bone or other structure.

Chemical attachment mechanisms may comprise, for example, a bioadhesiveor glue, cement, tape, tissue adhesives, or similar mechanism. Chemicalattachment mechanisms may further comprise mechanisms that facilitatecross-linking. In further embodiments, attachment mechanisms such ascrimping, welding, soldering, or brazing may be used. Further,attachment may be achieved via friction.

In some embodiments, biological attachment may be via mechanisms thatpromote tissue ingrowth such as by a porous coating or ahydroxyapatite-tricalcium phosphate (HA/TCP) coating. Generally,hydroxyapatite bonds by biological effects of new tissue formation.Porous ingrowth surfaces, such as titanium alloy materials in a beadedcoating or tantalum porous metal or trabecular metal may be used andfacilitate attachment at least by encouraging bone to grow through theporous implant surface. These mechanisms may be referred to asbiological attachment mechanisms.

Any of the various attachment mechanisms may be provided as part of thecovering or may be supplied separately. In various embodiments, theattachment mechanisms may be integral to the covering. Alternatively,the attachment mechanisms may be secured to the covering, for example,by stitching, welding, crimping, or other. The attachment mechanisms mayhave any suitable geometric configuration and may optionally includeapertures for receiving other components for coupling in vivo, such asan aperture for receiving a screw. Thus, for example, an attachmentmechanism may be provided configured for receiving an anchor forfixation to bone. Generally, any number of attachment mechanisms may beprovided at any suitable location on the covering.

The attachment mechanisms may be manufactured of the same material asthe portion of the covering to which it is coupled or may bemanufactured of a different material from the portion of the covering towhich it is coupled. The attachment mechanism may be resorbable ornonresorbable. The material of the attachment mechanism may be selectedto allow anchoring the covering to an adjacent covering having acomplementary attachment mechanism or to another structure. In variousembodiments, the attachment mechanism may comprise, allograft, syntheticmaterials, demineralized bone, nondemineralized bone, other material, orcombinations of these. The shape and size of the attachment mechanismmay be selected based on application.

In some embodiments, the covering may be tubular and have threaded endssuch that the ends may be threaded with a reciprocal thread of a furtherdevice or implant. For example, the covering may be used withinterference screws. In some embodiments, the covering may includeextensions or tabs that may be used for wrapping around or suturing tothe surgical site. Alternatively, the covering may be sutured directlyto the surgical site. The ends of the covering may be presealed or maybe sealed after introduction of contents. Sealing may be done by usingadhesives, heating, solvent treatment, suturing, knotting, or any othermeans.

Packing

The substance may be packed in the covering at any suitable density. Forsome applications, the substance may be loosely packed in the coveringto enhance manipulability. In some embodiments, the material may bepacked in the covering such that the covering retains flexibility andmay be folded over itself. In other applications, the substance may betightly packed in the covering to provide a relatively stiff deliverysystem, and it may be weight bearing. In some embodiments, the coveringmay be configured to facilitate placement of graft material in thecovering as was illustrated in FIGS. 1-8 described herein.

IV. Substance for Delivery by Covering

A substance is provided in the covering, before or during surgery (asdescribed below), for delivery in vivo. Generally, the substance ormaterial may be homogenous or heterogeneous. The substance or materialmay be selected to exhibit certain gradients. For example, the substanceor material may be selected to exhibit a gradient to guide, lure, orattract cells along a pathway. Such gradient may comprise a cellgradient, a cell type gradient (for example transitioning from bonecells to cartilage cells or transitioning from bone cells to tendoncells), a gradient of conductivity, or a gradient of density/porosity.In some embodiments, the substance or material may comprise a sequenceof ingredients.

The covering may be used to deliver a substance comprising any suitablebiocompatible material. In specific embodiments, the covering may beused to deliver surface demineralized bone chips (cortical orcancellous), optionally of a predetermined particle size, demineralizedbone fibers, optionally pressed, and/or allograft. For example, incertain embodiments, the ratio of DBM fibers to DBM chips is about30:70. In various embodiments, the ratio of fibers to chips, particlesor powders can be from about 5, 10, 15, 20, 25, 30, 35, 40, or 45 fibersto about 30, 35, 40, 45, 50, 55, 60, 65, or 70 chips.

In some embodiments, the demineralized bone material in the coveringcomprises from about 1 to about 70 micrometers particle size range orfrom about 125 to about 250 micrometer particle size range.

In some embodiments, the covering may have a modulus of elasticity inthe range of about 1×10² to about 6×10⁵ dynes/cm², or 2×10⁴ to about5×10⁵ dynes/cm², or 5×10⁴ to about 5×10⁵ dynes/cm². After the cover isadministered to the target site, the covering may have a modulus ofelasticity in the range of about 1×10² to about 6×10⁵ dynes/cm², or2×10⁴ to about 5×10⁵ dynes/cm², or 5×10⁴ to about 5×10⁵ dynes/cm².

For embodiments wherein the substance is biologic, the substance may beautogenic, allogenic, xenogenic, transgenic, or combinations of these.Each of these tissue types includes any tissue of bone origin,connective tissue origin, or any collagen containing material includingorgan tissues. Other suitable materials that may be positioned in thecovering include, for example, protein, hormones, nucleic acid,carbohydrate, lipids, collagen (autograft, allograft, or xenograft frommusculoskeletal or organ systems), allograft bone, autograft bone,cartilage stimulating substances, allograft cartilage, TCP, TCP/calciumsulfate, calcium carbonate, calcium phosphates, bioactive glasses, glassceramics, magnesium phosphates, phosphates containing any biocompatiblemetal ion, porous implants of all types including trabecular metal,biocompatible metals including stainless steel, cobalt-chrome, titanium,titanium alloys, polymers such as polylactic acid, polyglycolic acid,polycaprolactone, polyglycolide-co-caprolactone, polyethylene oxide,polypropylene oxide, polyglycolide-co-trimethylene carbonate,poly(lactic-co-glycolic acid), poly-L-lactide, polyethylene glycol,polyetheretherketones, polyurethanes, polyethers of all types, polyethylene terephthalte, polyethylene, polypropylene, Teflon, chondroitinsulfate, hyaluronic acid and its salts, chitosan and derivatives,natural polymers such as silk, collagen, polysaccharides,polyhydroxyalkanoates, polymers combined with bone or collagen or bothfrom any source (allograft, xenograft, transgenic, autograft),hydroxyapatite, calcium sulfate, polymer, nanofibrous polymers, growthfactors, carriers for growth factors, growth factor extracts of tissues,demineralized bone matrix, dentine, bone marrow aspirate, bone marrowaspirate combined with various osteoinductive or osteoconductivecarriers, concentrates of lipid derived or marrow derived adult stemcells, umbilical cord derived stem cells, adult or embryonic stem cellscombined with various osteoinductive or osteoconductive carriers,transfected cell lines, bone forming cells derived from periosteum,combinations of bone stimulating and cartilage stimulating materials,committed or partially committed cells from the osteogenic orchondrogenic lineage, platelets, activated platelets, antibiotics,substances with antimicrobial properties, or combinations of any of theabove. In accordance with one embodiment, the substance is a bone matrixcomposition such as described in U.S. patent application Ser. No.12/140,044 and U.S. Patent Publications Nos. 2007/0098756 and2007/0110820 all for Bone Matrix Compositions and Methods, hereinincorporated by reference in their entireties. Suitable materials forpreparing biocomposites for placement in the covering are disclosed inU.S. Patent Publication Nos. 2007/0191963, 2006/0216323, and2005/0251267, U.S. Pat. Nos. 6,696,073, 6,478,825, 6,440,444, and6,294,187, all herein incorporated by reference in their entireties forall purposes.

In some embodiments, the substance or material for delivery may comprisea biodegradable polyester such as poly(lactic acid) (PLA), poly(glycolicacid) (PGA), poly(lactic-co-glycolic acid) (PLGA), orpolyhydroxyalkanoates (polyhydroxybutyrates and polyhydroxyvalerates andcopolymers), polysaccharides, polyhydroxyalkanoates,polyglycolide-co-caprolactone, polyethylene oxide, polypropylene oxide,and polyglycolide-co-trimethylene carbonate. In some embodiments,poly(ethylene glycol) (PEG) may be incorporated into the biodegradablepolyester to add hydrophilic and other physico-chemical properties toenhance drug delivery. In some embodiments, composites of allograft boneand biodegradable polymers (for example, PLEXUR® products available fromOsteotech) may be delivered by the covering.

In some embodiments, the substance may be pressed before placement inthe covering. A substance provided within the covering may behomogenous, or generally a single substance, or may be heterogeneous, ora mixture of substances. In some embodiments, the substance may bedesigned to expand in vivo. U.S. Patent Publications No. 2008/0091270describes an osteoimplant that expands in vivo and is hereinincorporated by reference in its entirety. Such an embodiment may beused to fill a space and create contact with congruent surfaces as itexpands in vivo, for example for interbody fusion. Thus, in someembodiments, the delivery system may be used in the disc space, betweenimplants, or inside a cage. In some embodiments, the substance mayinclude a natural and/or synthetic expandable material. The expandablematerial may comprise bone particles, a polymer, a hydrogel, a sponge,collagen, or other material. In various embodiments, the expandablematerial comprises bone allograft comprising demineralized boneparticles, and the demineralized bone particles may be a blend ofcortical and cancellous bone. For example, the expandable material maycomprise demineralized cortical fibers and demineralized cancellouschips, wherein the demineralized cancellous chips may create a healthymatrix for the incorporation of new bone and add advanced expansioncharacteristics.

In addition to bone particles, an expandable polymer, a collagen sponge,compressed and/or dried hydrogels, or other materials may be used. Inaddition to expansion properties, the material may exhibitosteoinductive and/or osteoconductive properties. For example,cancellous bone particles may exhibit osteoconductive properties whiledemineralized cortical bone particles may exhibit osteoinductiveproperties.

The expandable material may be compressed during formation to aid insubsequent expansion. Generally, increased compression leads toincreased expansion characteristics in the osteoimplant. Compressedmaterials and certain non-compressed materials may be constrained suchthat, absent the constraint, the material is free to expand. Aconstrained material is one that embodies energy, such as a bent,spring-loaded, or coiled material, or any other material that isartificially prevented from expanding or conforming to its naturalconfiguration. The expandable material may include a covering materialthat partially or wholly surrounds the material. The covering materialmay be provided also expand as the expandable material expands.

Expansion may be activated in any suitable manner. For example,expansion may be activated by exposure to air, water, blood, heat,removal of a constraint, or otherwise. In one embodiment, the expandablematerial may be provided compressed and dried. Upon exposure to liquidin vivo, the expandable material may expand. In another embodiment, theexpandable may be compressed and at least partially constrained by acovering material. Upon exposure to liquid in vivo, the coveringmaterial may expand or disintegrate, as the expandable material expands.The expandable material may expand as a function of time. In yet anotherembodiment, the expandable material may have a first state atapproximately 60° F. and an expanded state at approximately 98° F. suchthat, upon implantation in vivo and exposure to body heat, theexpandable material may expand. In a further embodiment, the expandablematerial may be vacuum-sealed during manufacture and, when unsealed andexposed to air, the expandable material may expand.

The covering retains the substance in place by pressure against thecovering. The covering thus may, in some embodiments, maintain particlesof substance in close proximity (for example, where the covering retainsa substance comprising bone particles). Generally, the ratio of coveringmaterial to substance for placement within the covering may be low. Forexample, in some embodiments, the ratio of covering material tosubstance, by weight, may be approximately 1:1,000, 1:100, 1:50, 1:25,1:1, or any suitable ratio that may be higher or lower than these.

In some embodiments the substance delivered by the covering may includeor comprise an additive such as an angiogenesis promoting material or abioactive agent. It will be appreciated that the amount of additive usedmay vary depending upon the type of additive, the specific activity ofthe particular additive preparation employed, and the intended use ofthe composition. The desired amount is readily determinable by oneskilled in the art. Angiogenesis may be an important contributing factorfor the replacement of new bone and cartilage tissues. In certainembodiments, angiogenesis is promoted so that blood vessels are formedat an implant site to allow efficient transport of oxygen and othernutrients and growth factors to the developing bone or cartilage tissue.Thus, angiogenesis promoting factors may be added to the substance toincrease angiogenesis. For example, class 3 semaphorins, e.g., SEMA3,controls vascular morphogenesis by inhibiting integrin function in thevascular system, Serini et al., Nature, (July 2003) 424:391-397,incorporated by reference herein, and may be included in the recoveredhydroxyapatite.

In accordance with some embodiments, the substance may be supplemented,further treated, or chemically modified with one or more bioactiveagents or bioactive compounds. Bioactive agent or bioactive compound, asused herein, refers to a compound or entity that alters, inhibits,activates, or otherwise affects biological or chemical events. Forexample, bioactive agents may include, but are not limited to,osteogenic or chondrogenic proteins or peptides; demineralized bonepowder; collagen, insoluble collagen derivatives, etc., and solublesolids and/or liquids dissolved therein; anti-AIDS substances;anti-cancer substances; antimicrobials and/or antibiotics such aserythromycin, bacitracin, neomycin, penicillin, polymycin B,tetracyclines, biomycin, chloromycetin, and streptomycins, cefazolin,ampicillin, azactam, tobramycin, clindamycin and gentamycin;bacteriaphages; immunosuppressants; anti-viral substances such assubstances effective against hepatitis; enzyme inhibitors; hormones;neurotoxins; opioids; hypnotics; anti-histamines; lubricants;tranquilizers; anti-convulsants; muscle relaxants and anti-Parkinsonsubstances; anti-spasmodics and muscle contractants including channelblockers; miotics and anti-cholinergics; anti-glaucoma compounds;anti-parasite and/or anti-protozoal compounds; modulators ofcell-extracellular matrix interactions including cell growth inhibitorsand antiadhesion molecules; vasodilating agents; inhibitors of DNA, RNA,or protein synthesis; anti-hypertensives; analgesics; anti-pyretics;steroidal and non-steroidal anti-inflammatory agents; anti-angiogenicfactors; angiogenic factors and polymeric carriers containing suchfactors; anti-secretory factors; anticoagulants and/or antithromboticagents; local anesthetics; ophthalmics; prostaglandins;anti-depressants; anti-psychotic substances; anti-emetics; imagingagents; biocidal/biostatic sugars such as dextran, glucose, etc.; aminoacids; peptides; vitamins; inorganic elements; co-factors for proteinsynthesis; endocrine tissue or tissue fragments; synthesizers; enzymessuch as alkaline phosphatase, collagenase, peptidases, oxidases, etc.;polymer cell scaffolds with parenchymal cells; collagen lattices;antigenic agents; cytoskeletal agents; cartilage fragments; living cellssuch as chondrocytes, bone marrow cells, mesenchymal stem cells; naturalextracts; genetically engineered living cells or otherwise modifiedliving cells; expanded or cultured cells; DNA delivered by plasmid,viral vectors, or other means; tissue transplants; autogenous tissuessuch as blood, serum, soft tissue, bone marrow, etc.; bioadhesives; bonemorphogenic proteins (BMPs); osteoinductive factor (IFO); fibronectin(FN); endothelial cell growth factor (ECGF); vascular endothelial growthfactor (VEGF); cementum attachment extracts (CAE); ketanserin; humangrowth hormone (HGH); animal growth hormones; epidermal growth factor(EGF); interleukins, e.g., interleukin-1 (IL-1), interleukin-2 (IL-2);human alpha thrombin; transforming growth factor (TGF-beta);insulin-like growth factors (IGF-1, IGF-2); parathyroid hormone (PTH);platelet derived growth factors (PDGF); fibroblast growth factors (FGF,BFGF, etc.); periodontal ligament chemotactic factor (PDLGF); enamelmatrix proteins; growth and differentiation factors (GDF); hedgehogfamily of proteins; protein receptor molecules; small peptides derivedfrom growth factors above; bone promoters; cytokines; somatotropin; bonedigesters; antitumor agents; cellular attractants and attachment agents;immuno-suppressants; permeation enhancers, e.g., fatty acid esters suchas laureate, myristate and stearate monoesters of polyethylene glycol,enamine derivatives, alpha-keto aldehydes, etc.; and nucleic acids.

In certain embodiments, the bioactive agent may be a drug. In someembodiments, the bioactive agent may be a growth factor, cytokine,extracellular matrix molecule, or a fragment or derivative thereof, forexample, a protein or peptide sequence such as RGD. A more completelisting of bioactive agents and specific drugs suitable for use in thepresent invention may be found in “Pharmaceutical Substances: Syntheses,Patents, Applications” by Axel Kleemann and Jurgen Engel, Thieme MedicalPublishing, 1999; the “Merck Index: An Encyclopedia of Chemicals, Drugs,and Biologicals”, Edited by Susan Budavari et al., CRC Press, 1996; andthe United States Pharmacopeia-25/National Formulary-20, published bythe United States Pharmacopeia Convention, Inc., Rockville Md., 2001.

In some embodiments the drug can be a statin. Examples of a usefulstatin for treatment of pain and/or inflammation include, but is notlimited to, atorvastatin, simvastatin, pravastatin, cerivastatin,mevastatin, velostatin, fluvastatin, lovastatin, rosuvastatin andfluindostatin (Sandoz XU-62-320), dalvastain, eptastatin, pitavastatin,or pharmaceutically acceptable salts thereof or a combination thereof.In various embodiments, the statin may comprise mixtures of (+)R and(−)S enantiomers of the statin. In various embodiments, the statin maycomprise a 1:1 racemic mixture of the statin. Anti-inflammatory agentsalso include those with anti-inflammatory properties, such as, forexample, amitriptyline, carbamazepine, gabapentin, pregabalin,clonidine, or a combination thereof.

Unless otherwise specified or apparent from context, where thisspecification and the set of claims that follows refer to a drug (e.g.,an anti-inflammatory agent, analgesic, or the like) this disclosure isalso referring to a pharmaceutically acceptable salt of the drugincluding stereoisomers. Pharmaceutically acceptable salts include thosesalt-forming acids and bases that do not substantially increase thetoxicity of the compound. Some examples of potentially suitable saltsinclude salts of alkali metals such as magnesium, calcium, sodium,potassium and ammonium, salts of mineral acids such as hydrochloric,hydriodic, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuricacids, as well as salts of organic acids such as tartaric, acetic,citric, malic, benzoic, glycollic, gluconic, gulonic, succinic,arylsulfonic, e.g., p-toluenesulfonic acids, or the like.

Generally, any suitable substance or material may be delivered usingcoverings as provided herein. Such substances may include bone,cartilage, tendon, ligament, muscle, skin, nerve, collagen, calciumsulfate (CaSO₄), calcium phosphate (CaPO₄), βTCP, hydroxyapatite,bioglass, silicon-containing calcium phosphates, cells, autograft, orother.

Particulate Substance

In some embodiments, a particulate substance may be delivered by thecovering. For example, the covering may be used to deliver a particulatebone graft.

Growth Factors or Other Active Substances

Growth factors or other active substances may be delivered by thecovering. Active substances may include, for example, growth factorssuch as BMP-2 (Infuse) and/or other growth proteins, as well as drugs,for example, antibiotics. In some embodiments, a carrier for the growthfactors or other active substances may be incorporated into the deliverysystem.

It will be apparent to those skilled in the art that variousmodifications and variations can be made to various embodimentsdescribed herein without departing from the spirit or scope of theteachings herein. Thus, it is intended that various embodiments coverother modifications and variations of various embodiments within thescope of the present teachings.

Sterilization.

The medical device and/or covering may be sterilizable. In variousembodiments, one or more components of the medical device and/orcovering are sterilized by radiation in a terminal sterilization step inthe final packaging. Terminal sterilization of a product providesgreater assurance of sterility than from processes such as an asepticprocess, which require individual product components to be sterilizedseparately and the final package assembled in a sterile environment.

In various embodiments, gamma radiation is used in the terminalsterilization step, which involves utilizing ionizing energy from gammarays that penetrates deeply in the device and/or covering. Gamma raysare highly effective in killing microorganisms, they leave no residuesnor have sufficient energy to impart radioactivity to the device. Gammarays can be employed when the device is in the package and gammasterilization does not require high pressures or vacuum conditions,thus, package seals and other components are not stressed. In addition,gamma radiation eliminates the need for permeable packaging materials.

In various embodiments, electron beam (e-beam) radiation may be used tosterilize one or more components of the device and/or covering. E-beamradiation comprises a form of ionizing energy, which is generallycharacterized by low penetration and high-dose rates. E-beam irradiationis similar to gamma processing in that it alters various chemical andmolecular bonds on contact, including the reproductive cells ofmicroorganisms. Beams produced for e-beam sterilization areconcentrated, highly-charged streams of electrons generated by theacceleration and conversion of electricity. E-beam sterilization may beused, for example, when the medical device and/or covering is includedin a gel.

Other methods may also be used to sterilize the device and/or coveringand/or one or more components of the device and/or covering, including,but not limited to, gas sterilization, such as, for example, withethylene oxide or steam sterilization.

Methods of Use.

The covering delivers the substance or substances in vivo. Such deliverymay be active, passive, by diffusion, or other. Active delivery mayinclude the degradation or decomposition of the covering with theinteraction of body fluids, extracellular matrix molecules, enzymes orcells. It may also include the cleavage of physical and/or chemicalinteractions of substance from covering with the presence of bodyfluids, extracellular matrix molecules, enzymes or cells. Further, itmay comprise formation change of substances (growth factors, proteins,polypeptides) by body fluids, extracellular matrix molecules, enzymes orcells.

The covering is loaded with the substance for placement in vivo. Thecovering may be pre-loaded, thus loaded at manufacture, or may be loadedin the operating room or at the surgical site. Preloading may be donewith any of the substances previously discussed including, for example,DBM, synthetic calcium phosphates, synthetic calcium sulfates, enhancedDBM, collagen, carrier for stem cells, and expanded cells (stem cells ortransgenic cells). Any other suitable method may be used for loading asubstance in the covering in the operating room or at the surgical site.For example, the substance may be spooned into the covering, thesubstance may be placed in the covering using forceps, the substance maybe loaded into the covering using a syringe (with or without a needle),or the substance may be inserted into the covering in any other suitablemanner. Specific embodiments for loading at the surgical site includefor vertebroplasty or for interbody space filler.

In various embodiments, loading in the operating room or at the surgicalsite can be done with any of these materials and further with autograftand/or bone marrow aspirate by adding the desired material through thefilling means or funnel, by gravity using a spoon and/or a plunger topush the material through. In some embodiments, the closing memberuseful for delivery systems described herein can incorporate a geometricring which provides a stiffening design so that container or pouch canremain in an open position for filling and the surgeon no longerrequires the use of other filling means, such as for example a funnel.(please verify)

For placement, the substance or substances may be provided in thecovering and the covering placed in vivo. In one embodiment, thecovering is placed in vivo by placing the covering in a catheter ortubular inserter and delivering the covering with the catheter ortubular inserter. The covering, with a substance provided therein, maybe steerable such that it can be used with flexible introducerinstruments for, for example, minimally invasive spinal procedures. Forexample, the osteoimplant may be introduced down a tubular retractor orscope, during XLIF, TLIF, or other procedures. In other embodiments, thecovering (with or without substance loaded) may be placed in a cage, forexample for interbody fusion.

In continuous tube embodiments, the surgeon may divide the tube into thedesired number of compartments, using a crimper, heat tool or other.Alternatively, in an embodiment wherein the tube is perforated into aplurality of compartments, the surgeon may select the number ofcompartments desired and cut along the applicable perforation. In someembodiments, some of the compartments may be prefilled with a substancefor delivery and other compartments may be empty for filling by thesurgeon. For example, ever other compartment between perforations may bepreloaded or filled. The osteoimplant thus may be customized by fillingthe empty compartments with a desired substance.

The covering may be used in any suitable application. In someembodiments, the covering may be used in healing vertebral compressionfractures, interbody fusion, minimally invasive procedures,posterolateral fusion, correction of adult or pediatric scoliosis,treating long bone defects, osteochondral defects, ridge augmentation(dental/craniomaxillofacial, e.g. edentulous patients), beneath traumaplates, tibial plateau defects, filling bone cysts, wound healing,around trauma, contouring (cosmetic/plastic/reconstructive surgery), andothers. The delivery system may be used in a minimally invasiveprocedure via placement through a small incision, via delivery through atube, or other. The size and shape may be designed with restrictions ondelivery conditions. In some embodiments, pieces of the covering can beseparated by pulling or tearing force applied along separation assistsif present in a multi compartment configuration and the pieces of thecovering can be used to surround the bone defect. For examples, 3 piecesof the torn covering can be placed around the bone defect to triangulatebone growth by the influx of cells, in, at or near the bone defect.

In some embodiments, the covering is flexible enough so that thecovering can be folded upon itself before it is implanted at, near or inthe bone defect.

An exemplary application for using a delivery system as disclosed isfusion of the spine. In clinical use, the covering and deliveredsubstance may be used to bridge the gap between the transverse processesof adjacent or sequential vertebral bodies. The delivery system may beused to bridge two or more spinal motion segments. The coveringsurrounds the substance to be implanted, and contains the substance toprovide a focus for healing activity in the body.

In other applications, the delivery system may be applied to transverseprocesses or spinous processes of vertebrae.

Generally, the delivery system may be applied to a pre-existing defect,to a created channel, or to a modified defect. Thus, for example, achannel may be formed in a bone, or a pre-existing defect may be cut toform a channel, for receipt of the delivery system. The covering may beconfigured to match the channel or defect. In some embodiments, theconfiguration of the covering may be chosen to match the channel. Inother embodiments, the channel may be created, or the defect expanded oraltered, to reflect a configuration of the covering. The covering may beplaced in the defect or channel and, optionally, coupled usingattachment mechanisms.

At the time just prior to when the delivery system is to be placed in adefect site, optional materials, e.g., autograft bone marrow aspirate,autograft bone, preparations of selected autograft cells, autograftcells containing genes encoding bone promoting action, can be combinedwith the covering and/or with a substance provided within the coveringprior to or during the surgical procedure. The osteoimplant can beimplanted at the bone repair site, if desired, using any suitableaffixation means, for example, sutures, staples, bioadhesives, screws,pins, rivets, other fasteners and the like or it may be retained inplace by the closing of the soft tissues around it.

It will be apparent to those skilled in the art that variousmodifications and variations can be made to various embodimentsdescribed herein without departing from the spirit or scope of theteachings herein. Thus, it is intended that various embodiments coverother modifications and variations of various embodiments within thescope of the present teachings.

What is claimed is:
 1. A method for preparing an osteogenic materialdelivery system comprising a covering for implantation into a bonedefect, the method comprising providing the covering having an elongatedcontainment having a first open end and second sealed end opposite eachother, the elongated containment defining an opening at said first end,the opening configured for receiving at least one bone graft substance,the at least one bone graft substance comprising fully demineralizedbone matrix fibers and surface demineralized bone chips in a 30:70 ratioof fibers to chips, filling the elongated containment with the at leastone bone graft substance, closing the elongated containment with aclosing member at a selected location, the closing member closing theelongated containment with the at least one bone graft substancesecurely disposed therewithin, and implanting the closed delivery systeminto a bone defect, wherein the size of the fully demineralized bonematrix fibers and surface demineralized bone chips are from about 125 to250 micrometers, wherein the delivery system further comprises anattachment mechanism for retaining the covering at the bone defect site,wherein the covering comprises a porous mesh bag, said porous mesh bagretaining the at least one bone graft substance for placement at thebone defect site and for facilitating transfer of cells into and out ofthe porous mesh bag, and wherein the closing member comprises drawingstrings, stitches, sutures, wing sutures, heat seals, adhesion, pressurefittings, coil ring, twist ties or combinations thereof.
 2. A method forpreparing a delivery system according to claim 1, wherein the elongatedcontainment has a shape selected from tubular, rectangular, or cube. 3.A method for preparing a delivery system according to claim 1, whereinthe covering or the closing member or both comprise a material selectedfrom bioerodible polymers, bioabsorbable polymers, biodegradablebiopolymers, synthetic polymers, copolymers or combinations thereof. 4.A method for treating a bone defect in a patient in need of suchtreatment utilizing an osteogenic material delivery system comprising acovering for implantation into said bone defect, the method comprising:implanting into the bone defect all or at least a portion of a coveringcomprising one or more biodegradable polymers, the covering being porousand comprising at least one compartment, the at least one compartmentcomprising an elongated containment having a first open end and secondsealed end opposite each other, the elongated containment defining anopening at said first end configured to receive at least one bone graftsubstance, the at least one bone graft substance comprising fullydemineralized bone matrix fibers and surface demineralized bone chips ina 30:70 ratio of fibers to chips, the elongated containment adapted toreceive slidably a closing member at a selected location along theelongated containment, the closing member closing the elongatedcontainment with the at least one bone graft substance securely disposedtherewithin, wherein the size of the fully demineralized bone matrixfibers and surface demineralized bone chips are from about 125 to 250micrometers, wherein the delivery system further comprises an attachmentmechanism for retaining the covering at the bone defect site, whereinthe covering comprises a porous mesh bag, said porous mesh bag retainingthe at least one bone graft substance for placement at the bone defectsite and for facilitating transfer of cells into and out of the porousmesh bag, and wherein the closing member comprises drawing strings,stitches, sutures, wing sutures, heat seals, adhesion, pressurefittings, coil ring, twist ties or combinations thereof.